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Cited by 1,117Cancer Genomics and DiagnosticsLung Cancer Treatments and MutationsChromatin Remodeling and Cancer

The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

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de Bruin, Elza C., McGranahan, Nicholas, Mitter, Richard, Salm, Max, Wedge, David C., Yates, Lucy, Jamal-Hanjani, Mariam, Shafi, Seema, Murugaesu, Nirupa, Rowan, Andrew J., Grönroos, Eva, Muhammad, Madiha A., Horswell, Stuart, Gerlinger, Marco, Varela, Ignacio, Jones, David, Marshall, John, Voet, Thierry, Van Loo, Peter, Rassl, Doris M., Rintoul, Robert C., Janes, Sam M., Lee, Siow-Ming, Forster, Martin, Ahmad, Tanya, Lawrence, David, Falzon, Mary, Capitanio, Arrigo, Harkins, Timothy T., Lee, Clarence C., Tom, Warren, Teefe, Enock, Chen, Shann-Ching, Begum, Sharmin, Rabinowitz, Adam, Phillimore, Benjamin, Spencer-Dene, Bradley, Stamp, Gordon, Szallasi, Zoltan, Matthews, Nik, Stewart, Aengus, Campbell, Peter, Swanton, Charles·2014·Science
DOI 10.1126/science.1253462
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Abstract

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

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  1. Soria J. C., Cruz C., Bahleda R., Delord J. P., Horn L., Herbst R. S., Spigel D., Mokatrin A., Fine G., Gettinger S., Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC). Eur. J. Cancer 49 (suppl. 2), 3408 (2013).

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Authors
de Bruin, E. C., McGranahan, N., Mitter, R., Salm, M., Wedge, D. C., Yates, L., Jamal-Hanjani, M., Shafi, S., Murugaesu, N., Rowan, A. J., Grönroos, E., Muhammad, M. A., Horswell, S., Gerlinger, M., Varela, I., Jones, D., Marshall, J., Voet, T., Van Loo, P., Rassl, D. M., Rintoul, R. C., Janes, S. M., Lee, S.-M., Forster, M., Ahmad, T., Lawrence, D., Falzon, M., Capitanio, A., Harkins, T. T., Lee, C. C., Tom, W., Teefe, E., Chen, S.-C., Begum, S., Rabinowitz, A., Phillimore, B., Spencer-Dene, B., Stamp, G., Szallasi, Z., Matthews, N., Stewart, A., Campbell, P., & Swanton, C.
Affiliations
  • Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.
  • Cancer Research UK (GB)
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Cancer Research UK London Research Institute, London WC2A 3LY, UK.
  • Universidad de Cantabria (ES)
  • Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
  • Papworth Hospital NHS Foundation Trust (GB)
  • University College London (GB)
  • Thermo Fisher Scientific (United States) (US)
  • Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
Corresponding author
  • McGranahan, Nicholas
  • Mitter, Richard
  • Salm, Max
  • Wedge, David C.
  • Yates, Lucy
  • Swanton, Charles
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2014-10-10
Volume
346
Issue
6206
Pages
251-256
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1253462
OpenAlex
W2108371618
Cited by
1,117
References
62
Citations by year
2026: 38 · 2025: 43 · 2024: 59 · 2023: 82 · 2022: 82 · 2021: 86 · 2020: 99 · 2019: 113 · 2018: 111 · 2017: 145 · 2016: 131 · 2015: 119 · 2014: 9
FWCI
43.17
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • UCrea (University of Cantabria) (acceptedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Prostate Cancer Foundation
  • Breast Cancer Research Foundation
  • Wellcome Trust (091730, 105104, 088340)
  • Cancer Research UK (259303, A11590, A4688, A17786, 17001, A19310, 17786, 18377)
  • National Institute for Health and Care Research (CL-2011-18-001)
  • Academy of Medical Sciences (AMS-SGCL7-Murugaesu)
  • University College London
  • European Commission (259303)
  • Rosetrees Trust (M35-F1-CD1)
  • Fonds Wetenschappelijk Onderzoek
  • Ministerio de Economía y Competitividad
  • Vlaamse regering
  • National Institutes of Health
  • Medical Research Council
  • NIHR Cambridge Biomedical Research Centre
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
non-small cell lung cancer, tumor evolution, intratumoral heterogeneity, driver mutations, copy number alterations, chromosomal translocation, APOBEC mutational signature, genome doubling, tumor latency, carcinogen exposure, genomic instability
MeSH terms
APOBEC-1 Deaminase, Carcinogens, Carcinoma, Non-Small-Cell Lung, Cytidine Deaminase, Humans, Lung Neoplasms, Mutation, Neoplasm Recurrence, Local, Prognosis, Smoking, Translocation, Genetic, Tumor Cells, Cultured, Gene Dosage, Genetic Heterogeneity, Evolution, Molecular, Genomic Instability

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